Newly opened this year, major accomplishments for the NNU were the recruitment of staff, installation and testing of neuromodulation equipment, training of staff, writing of software to implement experiments and collect and process data, and protocol development. We now have a fully functional noninvasive neuromodulation laboratory ready for use with human subjects installed in the inpatient unit in the Clinical Center. Training staff in the safe and effective delivery of neuromodulation is one of our major functions as a Service within the Multi-Modal Imaging Center. To date, 67 individuals have received in-service training on TMS safety, 37 hands-on training sessions have been provided, 20 distinct individuals have received intensive hands-on training sessions (6 from NINDS and 14 from NIMH) including physicians, neuroscientists, advanced practice nurses, and students. Hands-on training sessions have covered the following procedures: Motor threshold determination, electromyography (EMG), Paired pulse TMS measures of cortical excitability, simultaneous TMS/EEG to measure TMS-evoked potentials, Somatosensory evoked potentials, Paired Associative Stimulation (a paradigm which induces neural plasticity, TMS-Safety procedures, and the role of Nursing in TMS and patient management. Our planned projects fall into 3 major themes: 1) measuring neuroplasticity, 2) modulating neuroplasticity, 3) modeling the effects of neuromodulation and mining multi-modal datasets to discover biomarkers of rapid antidepressant response. Our projects include: Theme 1: Measuring Neuroplasticity Mechanisms of Rapid Antidepressant Action collaboration with Drs. Zarate and Park o This project develops biomarkers of rapid antidepressant response through the addition of TMS-EMG, TMS-EEG and TMS-fMRI neuroplasticity measures to existing intramural research program on ketamine, and adding a seizure therapy comparison arm. Theme II: Modulating Neuroplasticity We are taking complementary approaches to modulating neuroplasticity: 1) seizure-induced neuroplasticity, 2) paired associative stimulation (PAS) and 3) novel tool development to extend the spatial and temporal specificity of noninvasive neuromodulation. Next generation seizure therapy collaboration with Drs. Zarate and Park o Therapeutically induced seizures exert rapid antidepressant action and are robust inducers of neurotrophic factors and neurogenesis. New technologies for focal seizure induction that we have developed extend the promise of improving the risk/benefit ratio by lowering cognitive side effects, and also provide the valuable scientific opportunity to examine common mechanisms across rapidly acting interventions such as ketamine. o This project involves optimization of seizure therapy dosing, through the study of individualized low amplitude seizure therapy (iLAST), comprised of focal seizure induction with minimal current exposure to improve tolerability of seizure therapy for depression. Cognitive Paired Associative Stimulation (C-PAS) o PAS has been shown to be a rapid inducer of Hebbian plasticity, strengthening synaptic efficacy within a circuit through repeated co-activation and coincident firing. Here we extend that approach to activate a targeted neural circuit through cognitive task performance (termed Cognitive Paired Associative Stimulation, or C-PAS), and couple that with simultaneous focal neuromodulation to enhance plasticity, as a means of enhancing circuit function and improving the functional-specificity of neuromodulation action. This represents a specific example of multi-modal intervention development, identified by a recent National Academy of Medicine report, to be a high impact area of science and a gap in our current research portfolio. One of our projects employs fMRI-guided TMS paired with a specific form of cognitive behavioral therapy for the treatment of depression (in collaboration with Dr. Strauman). Another of our projects, being conducted in the form of a cooperative agreement (5U01AG050618) uses fMRI-guided TMS with simultaneous working memory training to enhance executive function in older adults (in collaboration with Drs. Appelbaum and Cabeza). Noninvasive focal deep brain stimulation (nfDBS) o Noninvasive brain stimulation is either focal and superficial, or deep and broad. Its utility as a clinical and research tool hinges on the ability to improve the spatial and temporal aspects of targeting. These projects address innovative approaches to improve the spatial resolution of TMS at depth, to precisely target deep brain structures and distributed networks of interest. These projects take complementary approaches, such as transsynaptic targeting, and thermal coupled TMS in which brain cooling is used to modulate superficial cortical excitability, enabling deeper brain effects of TMS while blocking superficial effects (in collaboration with Dr. Hallett, NINDS). Theme III: Modeling Neuroplasticity / Mining Multi-Modal Datasets Our team comprises engineering expertise to perform in silico modeling of the spatial and temporal effects of neuromodulation on neuronal function, and to apply machine learning and graph theoretical approaches to data-mining and hypothesis generation to support the discovery of common mechanisms across rapidly acting antidepressant interventions. Examples of our modeling projects in collaboration with extramural investigators include: Christopher Abbott, MD, University of New Mexico Engaging Medial Temporal Lobes with Variable Amplitude Seizure Therapy to Improve Clinical Outcomes This proposed study explores the impact of targeted hippocampal engagement with varying levels of seizure therapy current amplitude in elderly patients with clinical, neuropsychological and neuroimaging assessments. Paul Croarkin, DO, MSCS, The Mayo Clinic Electric Field Induced by TMS in Adolescents with Major Depressive Disorder Little is known about the difference in TMS induced electric field strength between different coil placement strategies. The goal of this study is to quantify the induced electric field at the dorsal lateral prefrontal cortex in a group of depressed adolescent patients. Marc Dubin, MD, PhD, Weill Cornell Medical College Effect of TMS on the Structural Connectome in Patients with Major Depressive Disorder Increasing evidence indicates that depression is accompanied by altered structural connectivity in the white matter. Here we assess the impact of repetitive transcranial magnetic stimulation treatment for depression on the structural brain network organization. Jeroen van Waarde, MD, PhD, Rijnstate Hospital, Netherlands Electric Field Distribution of Seizure Therapy in Realistic Human Head Models This study examines the strength and spatial distribution of the electric field induced in the brain by seizure therapy using realistic head models constructed from more than 60 individual brain scans of depressed patients receiving seizure therapy. Andrew D. Krystal, MD, MS, University of California, San Francisco Evoked Potentials as Markers of Ketamine-Induced Cortical Plasticity in Patients with Major Depressive Disorder This open-label trial evaluates the utility of somatosensory, motor, and transcranial magnetic stimulation-based evoked potentials as markers of cortical plasticity in response to a single intravenous infusion of ketamine in patients with depression. Valerie Voon, MD, PhD, University of Cambridge Modulation of Resting Connectivity Between the Mesial Frontal Cortex and Basal Ganglia The mesial prefrontal cortex, cingulate cortex and the ventral striatum are key nodes of the human mesial frontal-striatal circuit involved in decision-making and executive function. Here we ask whether deep TMS targeting the mesial prefrontal cortex influe